The influence of sex hormones on renal cell carcinoma

Kidney cancer is a common malignancy that constitutes around 5% of all cancer cases. Males are twice as likely to acquire renal cell carcinoma (RCC) compared to females and experience a higher rate of mortality. These disparities indicate that sex hormone (SH)-dependent pathways may have an impact on the aetiology and pathophysiology of RCC. Examination of SH involvement in conventional signalling pathways, as well as genetics and genomics, especially the involvement of ribonucleic acid, reveal further insights into sex-related differences. An understanding of SHs and their influence on kidney cancer is essential to offer patients individualized medicine that would better meet their needs in terms of prevention, diagnosis and treatment. This review presents the understanding of sex-related differences in the clinical manifestation of kidney cancer patients and the underlying biological processes.


Introduction
Renal cell carcinoma (RCC) represents around 5% of newly diagnosed cancer cases in men and 3% in women, ranking the sixth most common malignancy in males and tenth in females with a more than doubled incidence over the past halfcentury in the developed world.Three main histological subtypes can be distinguished, with the most common being clear cell RCC (ccRCC), followed by papillary RCC (pRCC) and chromophobe RCC (chRCC). 1 Most cases are discovered incidentally during imaging, leading to a survival rate being dependent on the stage at diagnosis.General risk and modifiable risk factors include obesity, smoking, poorly controlled hypertension and renal failure.
Underlying genetic predispositions significantly contribute to tumour development, further course of the disease and even therapy response.An example that has fundamentally changed the therapy approach in RCC is the finding of mutations in the gene.The VHL gene mutations are associated with the Hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF) signalling pathway, which results in the overexpression of VEGF and platelet-derived growth factor (PDGF) receptors. 2,3[15][16][17][18][19][20] In addition to characteristics such as vascularization and immunogenicity, emerging evidence highlights the importance of sex hormone (SH) signalling in various solid tumours.Previous pan-cancer analyses have identified sex-specific characteristics in the tumour microenvironment (TME), impacting tumour mutation burden (TMB), immune cell counts, immune checkpoint genes and related functional pathways in the TME. 21SH and their corresponding receptors, including the androgen receptor (AR), oestrogen receptor (ER) and progesterone receptor (PR), act as ligand-dependent transcription factors and play critical roles in cellular growth and differentiation, both in neoplastic and non-neoplastic states. 22oreover, there is increasing evidence that these receptors can also stimulate gene expression through pathways that are independent of ligand interactions. 238][39][40][41][42] Conversely, female SHs oestrogen (E2) and PR may inhibit tumour cell proliferation and migration, primarily by inducing apoptosis, thereby reducing the risk of tumour development in certain contexts.[45][46][47] As with many neoplasms, RCC is more common in men, suggesting that underlying sex-specific pathophysiology and pathways may underlie the epidemiological differences in tumour development. 48,49Initial findings indicate that hormones also play a role in the development and progression of RCC. 50The implication of the role of steroid receptor signalling pathways has been described similarly, as regression of metastatic RCC during the administration of progestin or androgen was reported. 51[57] Nevertheless, it has shown to be crucial to elucidate and gain a more detailed understanding of the hormonal-molecular pathway mechanisms involved in RCC development and progression to further promote individualized tumour prevention and treatment strategies.Furthermore, although the role of ICI in the primary therapy setting will not as quickly be displaced, potential as well as supportive or alternative treatments will be discussed.As sex therefore entails both individual genetic and pathophysiological attributes, we aim to describe, understand and analyse the role of sex itself and SH in kidney cancer formation.

Methods
Literature research was conducted between January 2023 and September 2023 to identify studies reporting on the association between SH and RCC development.The search was performed using commonly used databases, including PubMed, Medline and Google Scholar.The study language was limited to English.The following medical subject heading terms were used to identify relevant results: 'kidney cancer', 'renal cell cancer', 'metastatic RCC', 'tumour microenvironment', 'sex hormones', 'steroid receptors', 'oestrogen', 'testosterone', 'progesterone', 'androgen', 'oestrogen receptor', 'androgen receptor', 'progesterone receptors', 'RNA', 'tyrosine kinase inhibitor', 'immunotherapy' and 'checkpoint inhibitor'.Thereafter, 38 on general topics and 151 studies that investigate specific aspects of the research area were included in this review.

SHs and signal transduction pathways in renal cell cancer
Signal transduction pathway-mediated processes refer to the series of molecular events that transmit signals from the cell surface to the nucleus, leading to specific cellular responses.These processes play a fundamental role in various biological functions, including cell growth, differentiation, proliferation and survival.Interaction with this mechanism by different signal molecules like AR, ER, PR and their ligands causes activation or inactivation of downstream signalling components. 58,59Here, we present evidence strongly suggesting that the interplay between the SH axis and signalling pathways implicated in oncogenesis, observed in other cancer types, may also have relevance in the development of RCC (Table 1).

Androgens
The androgen signalling axis is described as a key player in the development and progression of prostate cancer, 26 which is recognizably already influenced by sex in its primary development.Yet, an increasing number of studies suggest a potential contribution in RCC as well, which is gender-independent at first glance.1][72][73][74] A noteworthy correlation between AR expression and lower pathological stage and grading at diagnosis, as well as subsequent better outcomes, has been described. 70,71,75,76ontroversially, studies have indicated worse oncological prognosis and overall outcome in correlation to AR expression 72,73,77 as well.
In this context, the AR has been identified as a potential co-regulator of the HIF2a/VEGF signalling pathway. 78Its activation induces HIF2α/ VEGF expression in RCC tumour tissue, RCC is widely recognized as a typical 'hot tumour', characterized by an abundant infiltration of CD8+ T cells in the TME. 79-81While a higher infiltration of CD8+ T cells predicts a better prognosis in many cancers due to their cytotoxic function, [82][83][84] this correlation does not apply to RCC patients. 85However, CD8+ T cells have distinct subtypes, with conventional cytotoxic CD8+ T cells having an anticancer role, whereas exhausted CD8+ T cells become dysfunctional.
Studies investigating sex bias have identified the exhausted and dysfunctional state of CD8+ T-cells in various cancers, including bladder, prostate and liver cancers.7][88] Investigations into the differences in the TME of RCC between male and female patients have revealed that male RCC TME exhibits higher infiltration and exhaustion of CD8+ T cells compared to females.Additionally, the crucial role of the androgen-AR axis in inducing CD8+ T-cell exhaustion in RCC could be shown. 89The presence of intratumoural neutrophils in RCC has been associated with a negative prognosis in RCC as well.High-grade RCC patients exhibited a higher degree of neutrophil infiltration in tumour tissue compared to low grade, indicating the potential role of cancerinduced immunosuppression in promoting cancer progression through the modulation of neutrophils. 90Focusing on N2 neutrophils, which are known to be involved in carcinogenesis, angiogenesis and immunosuppression, Song et al. 62 described their ability to promote RCC proliferation by upregulating AR expression via the AR-c-Myc signalling pathway.
Moreover, high levels of dihydrotestosterone (DHT) receptors were found more often in higher staged RCC tumours. 91 Oestrogen receptor-α.Genetic variations within the ER-α gene have a notable role in RCC development.An exploratory analysis of 113 RCC cases revealed differences in genotype distribution at codon 10 on exon-1 of the ER-α gene compared to healthy individuals. 104,105ERα36 is known to be another splice variant, found in the cytoplasm and plasma membrane.Elevated ERα36 levels in these locations are linked to adverse prognostic factors in RCC, including poor disease-free survival, larger tumour size and advanced clinical stages. 46,106complex underlying interaction in the RCC formation involves the interplay between ER-α, VHL, HIF-1α and p53.ER-α is assumed to be a target for proteasomal degradation by the tumour suppressor von Hippel-Lindau protein (pVHL) E3 ligase.Overexpression of pVHL suppresses ER-α in RCC, while pVHL downregulation increases ER-α expression. 64Elevated ER-α expression has been found to enhance the activity of the HIF-1α transcription factor.In VHLdeficient cells, the expression of both ER-α and HIF-1α persists, and blocking ER-α using its inhibitor can effectively inhibit the proliferation of VHL-deficient cells.Notably, the anti-proliferative effect of faslodex, an ER-α inhibitor, in VHLdeficient cells by inducing the expression of p53 could be demonstrated. 64ER-α furthermore promotes the transcription of growth-related factors, driving gene expression, mitosis, proliferation, cancer development and tumour progression. 54e G-protein-coupled oestrogen receptor (GPER), distinct from nuclear ER, also plays a role in oestrogen-dependent development and progression of cancers, including RCC. [107][108][109][110] RCC cell lines express GPER abundantly and its activation promotes RCC cell migration and invasion by upregulating matrix metalloproteinase-2 (MMP-2) and MMP-9, as well as activating downstream signalling pathways, particularly MAPK and PI3K/AKT, promoting cell migration via the PI3K/AKT/MMP-9 pathway. 66 Oestrogen receptor-β.The role of ERβ remains controversial.2][113] However, initial investigations suggest that ER-β signalling appears to have a tumour-suppressive role in RCC 114 characterized by anti-proliferative functions, inhibition of migration, suppression of invasion and enhancement of apoptosis. 54,67,103e inhibitory effects of oestrogen via ER-β activation in RCC involve dampening downstream hormone signalling, including AKT, extracellular signal-regulated kinase (ERK) and janus kinase (JAK) activation, while increasing the expression of apoptotic genes such as BH3 interactingdomain death agonist (Bid), Caspase-3, Caspase-8 and Caspase-9. 54,67Conversely, subsequent investigations revealed the contrary role of ER-β in RCC.Clinical data showed increased ER-β expression in advanced-stage or high-grade tumours, correlating with unfavourable survival outcomes and reduced disease-free survival for RCC patients. 68,69,115,116ER-β has been identified as a promoter of RCC cell invasion through the augmentation of the TGF-β1/SMAD3 signalling axis.Targeting this pathway with anti-oestrogens or TGF-β receptor inhibitors effectively reduced RCC tumour growth and invasion. 68ER-β was also found to regulate Angiopoietin-2 (ANGPT-2) in RCC cells through oestrogen response elements (EREs) on the ANGPT-2 promoter.The escalated ANGPT-2 levels in RCC cells exert a stimulatory influence on angiogenesis by engaging and phosphorylating the Tie-2 receptor, leading to the formation of HUVEC tubes.Targeting the ER-β/ ANGPT-2/Tie-2 pathway with faslodex-enhanced RCC sensitivity to the TKI sunitinib treatment emerges as a promising therapy strategy. 69ER-β signalling has been implicated in inducing the VEGFa/HIF2α pathway as well. 65Infiltrating immune cells, particularly T cells, can modify ER-β expression and can promote RCC invasion.T-cell co-cultures with RCC cells resulted in elevated levels of T-cell-attracting factors, including IFN-γ, C-C motif chemokine ligand (CCL) 3 and CCL5, suggesting the establishment of a positive regulatory feedback mechanism.Simultaneously, infiltrating T cells appears to contribute to RCC cell invasion by influencing ER-β expression and concurrently suppressing the expression of DAB2IP.Intriguingly, the suppression of DAB2IP could subsequently reverse the T-cell-mediated promotion of RCC cell invasion. 117The interaction in this course concerning immunotherapy treatment with the checkpoint inhibitor nivolumab in RCC patients has been recently described.This therapeutic approach, which elicits immunomodulatory effects on neutrophils, has been found to induce alterations in the expression of sex SH, particularly oestrogen, during the treatment in patients with mRCC. 118Notably, an intriguing observation emerged with the administration of TKIs sunitinib and axitinib, leading to increased expression and stability of ER-β in RCC cell lines. 119,120ogesterone Progesterone signalling axis has also been shown to potentially influence the development of RCC.

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6 journals.sagepub.com/home/tamcarcinomatous kidney tissue, with varying levels in different histological RCC subtypes. 51,121,122R presence is reported in benign renal tumours and metaplastic nodules, 121 at a high rate than in malignant tumours of the kidney.Higher levels of expression were notably observed in cases of renal oncocytoma (RO). 60Literature also suggests that PR demonstrates nuclear reactivity in a range of 10%-50% of tumour cells across all RO cases.Interestingly, up to 20% higher PR expression has been described in chRCC.In comparison, nonneoplastic renal tissue displays scattered stromal cells and tubular cells that show reactivity for both ER and PR, as in comparison fewer than 1% of RCC cases show reactivity for these receptors. 123ogestin and adipoQ receptor  130,131 The following chapters will present current findings on the connection between ncRNA and the signalling pathways of SH, analysing their potential involvement in the progression of RCC (Table 2 and Figure 1).

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Volume 16 corresponding gene, ASS1, by competing with miRNA-34a-5p.Reduced ASS1P3 expression inhibited ASS1 by miRNA-34a-5p, resulting in increased cell proliferation.Although a direct correlation between AR and ASS1P3 expression was not detected by the authors, it was postulated that AR may physically interact with ASS1P3, thereby impeding the interaction between ASS1P3 and miRNA-34a-5p. 132Bai et al. 133 investigated the relationship between the lncRNA known as HOX transcript antisense intergenic RNA (HOTAIR) and AR in human ccRCC.HOTAIR is a transacting lncRNA located on chromosome 12q13.13,with a regulatory boundary in the HOXC cluster. 1394][145] The Hedgehog-GLI (HH-GLI) signalling pathway has been implicated in promoting cellular proliferation, differentiation, vascularization and stem cell maintenance.In RCC, GLI1/2 is activated by PI3K/AKT signalling. 146ere, it was shown that GLI2 serves as a target gene for both HOTAIR and AR synergistically.HOTAIR and AR cooperatively bind to the GLI2 promoter, leading to an increase in its transcriptional activity.Consequently, GLI2 and its downstream genes, including cancer stem cell (CSC) transcription factors, vascular endothelial growth factor A (VEGFA) and PDGFA, were upregulated.This upregulation promotes tumour angiogenesis and enhances cancer stemness in RCC cells both in vitro and in vivo. 133RNA-143-3p, identified as a tumour suppressor, is frequently down-regulated in various cancers, including RCC. [147][148][149][150] Its decreased expression has been associated with the promotion of RCC cell invasion, migration and proliferation through downstream signalling molecules, including AKT, MMP-13, K-RAS and P-ERK.In a study by Zhai et al.AR influence of miRNA-143-3p expression by direct binding to its potential androgen response elements (AREs) in its promoter, thereby transcriptionally suppressing miRNA-143-3p was discovered.Additionally, a long noncoding RNA called suppressing AR in RCC (lncRNA-SARCC) was identified to directly bind and suppress the AR function by post-transcriptionally modulating the AR protein, consequently increasing miRNA-143-3p expression and suppressing the RCC progression.Consequently, expression of lncRNA-SARCC was found to be reduced in ccRCC and metastatic ccRCC compared to surrounding nontumour and non-metastatic tissues, and this reduction correlated with a poorer prognosis in ccRCC patients.Interestingly, the authors observed that Sunitinib induces the expression of lncRNA-SARCC, thereby reducing the resistance of RCC cells to this drug. 134An additional suppressive effect of LncRNA-SARCC on RCC development could be revealed through its regulation of the AR/HIF-2α/C-MYC axis signalling pathway.Interestingly, the expression of lncRNA-SARCC was found to be mediated differently in response to hypoxia.(1) Function via altering circRNA with inhibiting effect of ER-β on transcription of circRNA, 116 promoting effect of ERβ on transcription of circRNA 120 and direct effect of AR on circRNA function. 137(2) The interaction between AR and lncRNA with chromatin has a synergistic effect on the activities that affect the intrachromosomal genes located nearby. 133(3) The effect of AR on miRNA expression occurs through the direct binding of its candidate AREs in the promoter region. 136(4) The function and stability of a protein is influenced by its interaction with lncRNA, thereby impacting interactions between the protein and miRNA. 134(5) Direct interaction with AR can regulate the ceRNA activity, resulting in an increased effect of the competing miRNA. 132urce: Created with BioRender.com.ARE, androgen response elements; ceRNA, competitive endogenous RNA; circRNA, circular RNAs; lncRNA, long noncoding RNA; miRNA, microRNA.
leading to a decrease in the HIF-2α/C-MYC axis and its cell proliferating and tumourigenic effect.In return, lncRNA-SARCC expression can be transcriptionally regulated by HIF-2α through its binding to hypoxia-responsive elements on the lncRNA-SARCC promoter, suggesting the presence of a negative feedback loop. 135

Oestrogens
As a transcription factor, ER-β can bind to specific DNA sequences in the promoter regions of target genes, either activating or repressing their transcription.ER-β was identified as a suppressor of circRNA ATPase plasma membrane transporter 2B1 (circATP2B1) expression by directly binding to the 5′ promoter region of its host gene ATPase plasma membrane Ca2+ transporting 1 (ATP2B1), which encodes circATP2B1.CircATP2B1 is implicated in regulating miRNA-204-3p in ccRCC cells, significantly increasing miRNA-204-3p by circATP2B1 addition.Moreover, circATP2B1 may function as a socalled 'reservoir' to stabilize miRNA-204-3p expression, as it interacts directly with miRNA-204-3p.This interplay results in elevated fibronectin 1 (FN1) expression in ccRCC cells, as miRNA-204-3p directly targets FN1 mRNA's 3′ UTR, suppressing FN1 protein expression.Inhibition of miRNA-204-3p increases FN1 expression, while miRNA-204-3p overexpression decreases FN1 levels in ccRCC cells.Analysis of the ccRCC patient survival data from the Cancer Genome Atlas indicates worse overall survival (OS) for patients with elevated ER-β and FN1 expression, while higher miRNA-204-3p expression correlates with significantly better OS, emphasizing the clinical relevance of the ER-β/ circATP2B1/miRNA-204-3p/FN1 axis in ccRCC progression. 116Furthermore, ER-β facilitates an increase in HOTAIR expression by binding to its promoter in RCC.Consequently, HOTAIR assumes a role in counteracting the effects of various miRNAs.Subsequently, HOTAIR counteracts the effects of several miRNAs.By antagonizing miRNA-138, (targeting ADAM9), miRNA-204 (targeting CCND2), miRNA-217 (targeting genes like VEGFA, VIM, ZEB1 and ZEB2) and miRNA-200c (targeting ZEB1 and ZEB2), it results in collective interaction with RCC cell, proliferation, migration and invasion. 115gher ER-β expression correlates with elevated VE-cadherin, a pivotal adhesion molecule in vasculogenic mimicry (VM) formation.VM is a process where tumour cells mimic blood vessel-like structures to secure nutrients and oxygen, potentially contributing to ccRCC progression and metastasis. 119

SHs and treatment of RCC
Androgen treatment in RCC The potential significance of the androgen-signalling axis in the progression of RCC has led to the thought that interfering with the hormonal axis may be a potential strategy to enhance patient survival.Clinical trials are already investigating the efficacy of therapeutic agents targeting AR in RCC.The BARE trial (Blockade of Androgens in RCC using Enzalutamide, NCT02885649, www.clinicaltrials.gov,accessed on 9 September 2021) was designed to elucidate the impact of the AR inhibitor enzalutamide on tumour growth prior to surgical resection.Regrettably, the trial was prematurely terminated due to unavailability of funding.
Flutamide, a nonsteroidal anti-androgen, was also investigated in patients with RCC.Among 25 cases treated, one patient exhibited partial remission and two patients experienced a state of stabilization of disease.Nevertheless, flutamide did not demonstrate any anti-tumour activity in individuals with metastatic RCC. 122Enzalutamide and abiraterone acetate, a CYP17A1 inhibitor that inhibits androgen production, showed more promising results in in vivo studies, demonstrating a substantial reduction in tumour size. 152ockdown of the epigenetic co-regulator lysinespecific histone demethylase 1, along with enzalutamide, slowed RCC growth and migration in a mouse model. 153In a patient-derived xenograft model with sunitinib-resistant RCC, AR upregulation was observed.Enzalutamide treatment led to AR degradation and decreased AR activity, resulting in effective tumour regression when combined with sunitinib. 154These findings highlight the importance of the androgen axis in RCC and suggest AR as a potential target for a therapeutic approach.
Oestrogen treatment in RCC Investigation on hormonal carcinogenesis, specifically highlighting the involvement of the SH in RCC pathogenesis, has yielded encouraging findings.Particularly outcomes in the domain of RCC therapy targeting ER remain promising, providing notable advantages for managing metastatic disease.
6][157] Conversely, the inhibitory impact on tumour formation was demonstrated with the antioestrogen agent nafoxidine. 158In vitro investigations proposed that potentially reactive oestrogen intermediates might act as instigators of experimental nephron-carcinogenesis, inducing substantial oxidative stress within renal cells upon prolonged oestrogen exposure. 159,160e potential utility of tamoxifen, a selective ER modulator commonly used in breast cancer treatment, was explored as a therapeutic approach for small cohorts of patients with RCC, yielding varied outcomes.In one study, 34 patients with progressive RCC were treated with high-dose tamoxifen (100 mg/ml 2 daily) until disease progression.An overall partial response of 10%, including one complete remission, was observed.Favourable survival outcomes were noted in patients with pulmonary metastases, good performance status and prior nephrectomy. 161other investigation involved 10 patients with advanced RCC treated using combined chemoendocrine therapy comprising tegafur, a prodrug of fluorouracil, and tamoxifen.Positive responses were observed, particularly in patients with ER-positive and ER-negative tumours. 162A comparison study evaluated tamoxifen alone against IL-2/IFN-α therapy combined with tamoxifen.
Although tamoxifen was included due to its nontoxic behaviour and potential enhancement of IL-2's anti-tumour activity, no significant survival differences were found between treatment arms. 163While high-dose tamoxifen demonstrated some anti-tumour effects in specific cases, combined hormonal therapy did not confer a significant therapeutic advantage for advanced RCC.Despite this, subsequent years have seen limited research exploring the potential of hormone modulators in RCC.This is noteworthy considering the emergence of new therapeutic strategies such as TKIs and immune-based therapies, which have shown promise in metastatic RCC management.

Progesterone treatment in RCC
Hormonal agents, like medroxyprogesterone, were found to have some effectiveness in treating metastatic RCC in early studies.[166] Sex and immunotherapy in RCC Previous research has shown differences in immune responses, particularly anti-tumour responses, between sexes. 167,1680][171] The controversially discussed data do not necessarily apply to RCC. 172,173 A recent comprehensive review focused on the efficacy of ICI in urological cancers, including RCC, indicating an improved OS, regardless of sex. 174Meanwhile, adjuvant ICI monotherapies reduce the risk of disease recurrence in women with locally advanced RCC, yet not in men.Furthermore, ranking analyses revealed distinct outcomes for RCC treatment between the sexes, suggesting that sex may influence clinical decision-making. 174However, there is evidence of a divergent response to ICI treatment in patients with advanced RCC, with a less marked effect observed in females compared to male patients, indicating that sex is a crucial factor in clinical decision-making. 175other intriguing aspect of sex differences lies in the occurrence of adverse events associated with ICI.Immunotherapy disrupts immune balance, potentially leading to immune-related adverse events (irAEs) affecting various organ systems. 176omen exhibit higher innate and adaptive immune responses than men, along with an increased susceptibility to autoimmune diseases, leading to a higher risk of irAEs. 177Consequently, female sex has been identified as a predictive biomarker for irAE occurrence in patients treated with ICIs. 178Notably, a study by Unger et al. 179 examining gender disparities in therapy responses, particularly to immunotherapy, revealed that women receiving immunotherapy exhibited a 49% greater risk of irAEs than men, with the severity of irAEs being higher among women.
Some further nuanced relationships between sex and molecular predictors of ICI response could be revealed.TMB has been associated with a positive ICI response in men with certain cancers such as melanoma, bladder, head and neck, and RCC. 180Conversely, other molecular markers, such as activated T-cell frequency and expression of immune checkpoint proteins, including both inhibitory (programmed cell death protein1 1 (PD-1), cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), Lag3) and stimulatory (OX40, ICOS, CD27) markers, are associated with a positive ICI response in female patients. 181 this context, SHs are suspected to influence the TME and underlie the differences in immune responses between men and women. 182E2 increases immunoglobulin production, while androgens such as dihydrotestosterone (DHT) and testosterone have been shown to reduce immune activity. 167Regulatory T cells (Treg) rise when E2 levels increase. 183Reduced levels of E2 encourage differentiation of T helper (Th) cells towards Th1, whereas higher levels of E2 promote the Th2 phenotype. 184Additionally, E2 is linked with heightened expression of PD-1. 183e persistence of androgen-induced exhaustion of CD8+ T cells may limit the efficacy of ICIs in male RCC, necessitating additional therapeutic strategies. 89Androgen deprivation therapy (ADT) M Ladurner, AK Lindner et al.
journals.sagepub.com/home/tam13 can prevent CD8+ T-cell exhaustion in the TME and improve the efficacy of ICIs, particularly anti-PD-1 treatment. 86,87Combination therapy with androgen receptor inhibitors (ARi) and ICIs has shown synergistic effects in RCC in vivo, possibly because ARi reverses androgen-induced immunosuppression in the TME of male RCC. 89ther investigations suggest that ADT can enhance the effectiveness of immunotherapy by modulating immune cell function. 185Moreover, studies have shown that dendritic cells are better able to stimulate T-cell responses when ADT is administered after immunotherapy.
Nevertheless, the regulatory impact of SH on immunotherapy in cancer, particularly the association between SH and ICI in metastatic RCC, has not been thoroughly evaluated.There is a notable lack of data and the interpretation is complicated, also due to the insufficient exploration of the reciprocal effects of checkpoint inhibition on SH and vice versa.However, anti-PD-L1 therapy has been shown to significantly downregulate SH levels in male mice, but not in female mice, thereby enhancing the anti-tumour efficacy of anti-PD-L1. 186In contrast, an increase in estradiol and luteinising hormone (LH)/ follicle-stimulating hormone (FSH) ratio in male patients receiving nivolumab monotherapy for metastatic RCC has been recently reported and an association between progression free survival (PFS) and objective response rate (ORR) with increased LH/FSH ratio during nivolumab therapy has been demonstrated. 118ditionally, survival outcomes among RCC patients may be influenced by gender-related factors such as behaviour, as well as genetics and hormones. 57,167,187Therefore, there is still an ongoing debate about sex-related differences in oncological outcomes for patients with metastatic RCC.Pooled meta-analyses may not fully capture the nuanced interactions of sex and ICI response.Further investigation into possible sexbased differences in the immune response to ICIs is essential for identifying patients who are most likely to benefit from particular ICI-based combination therapies.

Summary and conclusion
Investigations of the pathobiology of sex steroid hormones and their receptors in RCC significantly expand our understanding of crucial aspects of RCC development and progression.
Currently, the molecular role of SH in RCC remains to be elucidated to provide a precise model of hormonal interactions with oncogenesis.Unfortunately, the limited number of publications in this area suggests that there is a lack of research priority.
As a physiological fact, variable expression of steroid receptors has been noted when comparing normal kidney tissue and RCC tissue, which is to be seen as the potential basis for the discovered differences in the development of RCC.SH signalling in RCC suggests a not yet fully understood multifaceted dual role, influencing processes such as proliferation, invasion, apoptosis and angiogenesis through distinct molecular mechanisms.In this review, we presented comprehensive examples of both the oncogenic and tumour-suppressive effects of SH in RCC.For instance, E2 has been observed to interact with various signalling pathways, including VEGF/ HIF2α, PI3K/AKT/MMP-9, TGF-β1/SMAD3 and ER-β/ANGPT-2/Tie-2, primarily through ER, whereas the activation of the AR has been linked to pathways involving PI3K/AKT → NF-κB → CXCL5, AR-c-Myc and STAT5 regulation.
Recent research has emphasized the critical role of ncRNAs in various biological functions and their profound impact on cancer, including RCC.Notably, the substantial influence of SH on the expression and functionality of numerous ncR-NAs involved in the complex process of RCC development has been highlighted.Although our understanding of ncRNA function in RCC is evolving, this review underscores their potential role in initiating, promoting and progressing RCC through different miRNA/target gene axes via activation of AR and ER.Their contribution to RCC development shown in this review highlights their importance as potential therapeutic targets and biomarkers for more effective RCC therapies.However, our understanding of ncRNA function in RCC, particularly in relation to steroid hormones, remains limited, and further research is needed to explore their full functional spectrum. 188,189e approval of a wide range of immunotherapies is considered to be the most significant breakthrough in the treatment of advanced RCC in recent years.However, it is to be noted that many exploratory studies investigating hormone manipulation as a potential strategy for the treatment of

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Volume 16

Figure 1 .
Figure 1.Schematic representation of potential interaction mechanisms between sex hormones and ncRNA regarding RCC formation.(1) Function via altering circRNA with inhibiting effect of ER-β on transcription of circRNA,116 promoting effect of ERβ on transcription of circRNA120 and direct effect of AR on circRNA function.137(2) The interaction between AR and lncRNA with chromatin has a synergistic effect on the activities that affect the intrachromosomal genes located nearby.133(3) The effect of AR on miRNA expression occurs through the direct binding of its candidate AREs in the promoter region. 136(4) The function and stability of a protein is influenced by its interaction with lncRNA, thereby impacting interactions between the protein and miRNA.134(5) Direct interaction with AR can regulate the ceRNA activity, resulting in an increased effect of the competing miRNA.132

Table 1 .
Studies characterizing sex hormone interactions with signalling pathways during cross-talk in renal cell cancer.

Table 2 .
Studies characterizing sex hormone interactions with ncRNA during cross-talk in renal cell cancer.

Table 2 .
(Continued) One supposed mechanism by which M Ladurner, AK Lindner et al.